While pediatric T-ALL is successfully treated in 80% of cases, the prognosis for the remaining 20% of cases in which relapse occurs continues to be dismal. Identification of prognostic biomarkers predicting an aggressive disease course or predicting a pattern of drug responsiveness would highly significant as it would enable both the identification of patients with aggressive disease and potentially provide therapeutic alternatives for the 20% of cases that do not respond to standard chemotherapy. Ribosomal proteins are increasingly understood to be important focuses of cellular regulation and transformation (e.g. RPS19 in Diamond Blackfan Anemia and RPS14 in 5q- Syndrome). We have evidence suggesting that inactivation of the gene encoding ribosomal protein Rpl22 may have prognostic value as a biomarker of aggressive disease in T-ALL. Indeed, we have found that approximately 10% of T-ALL examined so far exhibit deletion of one Rpl22 allele and that these deletions are enriched in patients that succumb to the disease. Moreover, we have recently provided evidence that loss of one allele of Rpl22 predisposes T lineage precursors to transformation in mouse models. Taken together, these findings support our hypothesis that Rpl22 is part of a signaling pathway that critically regulates either transformation or disease progression in T-ALL. The current proposal seeks to determine whether Rpl22 inactivation has value as a biomarker of prognosis or therapeutic responsiveness. We will do so according to 2 aims. In Aim 1, we will investigate the extent to which Rpl22 is inactivated in an expanded cohort of human T-ALL patient samples by performing aCGH analysis and sequencing of the Rpl22 alleles. We will also evaluate the impact of Rpl22 inactivation on therapeutic responsiveness in a panel of 13 T-ALL cell lines derived from relapsed patients, 1/4 of which exhibit single inactivating point mutations in Rpl22. We will test responsiveness to standard T-ALL therapies as well as inhibitors of mTOR, since mTOR is common downstream node of the two most frequently activated signaling pathways in T-ALL, and PI-3 kinase. In Aim 2, we will assess the role of Rpl22 inactivation in transformation using mouse models bearing oncogenic mutations frequently observed in T-ALL. From these studies we expect to gain insight into whether inactivation of Rpl22 serves as a prognostic biomarker which can inform the course of therapy in relapsed disease. PUBLIC HEALTH RELEVANCE: Insights into the value of Rpl22 inactivation as a biomarker of prognosis or therapeutic responsiveness would be an important advance in managing the clinical care of T-ALL patients with an aggressive disease course.